Side Effects of Loxapine Aerosol Raise FDA Concerns

WASHINGTON -- Although staccato loxapine (Adasuve) appears to be effective in calming schizophrenic and bipolar patients, concerns remain about the drug's pulmonary side effects, according to a review by FDA staff members.

Staccato loxapine is an inhalable formulation of a thermally generated aerosol of loxapine. It is a new dosage form of loxapine, an antipsychotic with dopamine-D2-blocking activity that has been available in the U.S. since 1975 (the earlier version is no longer being marketed).

The "staccato" version has been developed by Alexza Pharmaceuticals, loxapine's manufacturer, for treatment of agitation in patients with schizophrenia or bipolar disorder.

Alexza applied for approval of the new formulation and its new indication in 2009. The FDA issued a "complete response" letter in 2010, saying that although the company had proved the drug's efficacy, it had not shown that staccato loxapine was safe to use, given that it was known to increase the risk of pulmonary adverse events such as bronchospasm. Patients with pre-existing respiratory conditions, such as asthma and chronic obstructive pulmonary disease (COPD), were particularly vulnerable.

The agency requested that the company conduct "a human factors study to assess usability of the product in settings involving representative providers and patients," as well as a "more realistic worst-case simulation test." It also said that even though the company had proposed a risk evaluation and management strategy (REMS) to screen for patients at risk and manage patients who receive the drug, as well as a post-marketing observational study, the FDA continued to be concerned that patients couldn't use the drug safely.

The company then submitted its response to the FDA's letter, and now the application is being brought before the advisory panel. At Monday's meeting, the Psychopharmacologic Drugs Advisory Committee will be voting on whether staccato loxapine has been shown to be "sufficiently effective" in treating agitation in patients with schizophrenia or bipolar disorder, and also whether it is safe enough to use in concert with the REMS that the company is proposing.

The FDA does not have to follow the advice of its advisory committees, but it usually does.

The efficacy claim for the drug was based on two phase III placebo-controlled clinical studies that investigated one to three doses of staccato loxapine (5 mg or 10 mg) in agitated patients with schizophrenia or bipolar disorder. Both studies allowed for second or third doses as needed over a 24-hour period.

Pulmonary safety was tested via three double-blind, placebo-controlled studies that looked at two 10-mg doses of loxapine in 30 healthy subjects with normal pulmonary function; in 52 patients with mild to persistent asthma; and in 53 subjects with chronic obstructive pulmonary disease. The two doses were separated by either eight or 10 hours.

Adverse events associated with loxapine were dysgeusia (about 13% of patients) and sedation (10.5%). Most adverse events were mild to moderate. Akathisia and tremor each occurred in two patients (0.4%). There also was one report of neck dystonia combined with oculogyration.

In the pulmonary safety trials, "significant pulmonary adverse events, particularly in subjects with asthma or COPD, were reported and are a major safety concern," the agency noted. In subjects with asthma, 18 loxapine-treated subjects (69%) and three placebo patients (12%) had "notable" respiratory signs or symptoms, defined as the forced expiratory volume in the first second (FEV1) decrease from baseline of ≥20%, an airway adverse event, or use of rescue (bronchodilator) medication.

Overall, about 54% of patients who had asthma and were treated with loxapine­ experienced airway adverse events, versus 11.5% of placebo-treated subjects. The most common airway adverse events in subjects with asthma were bronchospasm (27%), chest discomfort (23%), wheezing (15%), and dyspnea (11.5%).

Airway adverse events also occurred in the trial involving COPD patients treated with loxapine, including dyspnea (11.5%), cough (11.5%), and wheezing (8%). Among the COPD patients treated with placebo, no similar adverse events occurred in more than a single patient.

"In a controlled study setting, obtaining an accurate history and physical, providing instructions on use of the device, and monitoring for the development of respiratory signs and symptoms may be easier than in a real world setting such as an acute presentation to an emergency room," the FDA reviewers noted.

The agency expressed doubt as to whether acutely agitated and, in many cases, psychotic patients presenting in a real-world setting could do the following:

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